The principal ingredient of Viread® tablets, a medication developed by Gilead Sciences Inc. (U.S.A.) and used to treat hepatitis B, has a general name of tenofovir disoproxil fumarate (hereinafter, referred to as “Teno-DF”); its melting point (MP) is 219° C., its MW is 635.52 and its chemical name according to the structural formula is 9-[2-(R)-[[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]]methoxy]propy 1] adenine fumarate.
The Teno-DF was approved by the U.S. FDA in 2001, for the treatment of HIV, and in 2008 (November), for the treatment of hepatitis B virus (HBV). It was also approved for use in Europe in 2008 (April) as a medication to treat hepatitis B virus (HBV) Teno-DF is a precursor drug prepared by providing a substituent of isopropylcarbonyl methoxy group as a structure of the lipophilic component into tenofovir in order to enhance the bioavailability of the tenofovir (MP 267-280° C., MW 287.21).
Hence, the most crucial issue in the synthesis of the Teno-DF is to synthesize the anti-viral major component tenofovir with high purity at high yield.
The base material used to synthesize tenofovir is hydroxypropyl adenine (HPA, ((R)-9-[2-(hydroxyl)propyl]adenine, MW. 193.2). It is the major challenge to minimize the formation of byproducts and degradation products in the synthesis of tenofovir from HPA.
As for tenofovir (phosphonomethoxypropyladenine, (R)-9-[2-(phosphonomethoxy)propyl]adenine, PMPA), the yield and purity of the final product tenofovir depends on the catalyzed chemical reaction of the ester product DEPMPA((R)-9-[2-(diethylphosphonomethoxy)propyl]adenine) formed in the methylation of phosphate that is one of the steps in the synthesis of tenofovir from HPA. But, severe difficulties are encountered in the process of synthesizing DEPMPA from HPA at high yield and hydrolyzing DEPMPA into tenofovir (PMPA) with high purity and many researches have been made on this issue to continuously develop excellent synthesis methods and produce papers and patents on this matter.
The catalyzed chemical reaction uses a combination of different alkali catalyst and involves different organic solvents and extraction methods according to the individual reactions.
A condensation reaction between diethyl-p-toluenesulfonyloxymethylphosphonate (DEPTSMP) that is a substance to introduce methylene phosphate molecules and HPA is activated in the presence of an alkoxide catalyst used as a condensation catalyst, starting from lithium butoxide to magnesium butoxide, magnesium isopropoxide, a composite catalyst of sodium amide and magnesium acetate, or butyl magnesium chloride. After the production of tenofovir with high purity at high yield using the catalyst, the formation of the precursor derivative Teno-DF through the subsequent reaction can occur according to the conventional method.
But, the high content of impurities in the tenofovir product may have an adverse effect on the reactions of the subsequent step for synthesizing Teno-DF to lower the stability of the products using the Teno-DF and produce a large amount of degradation products exceeding the acceptable level, remaining highly deliquescent substances difficult to filter out in the step of separation of residues formed as byproducts in the reaction step and thus causing a considerable difficulty in commercialization based on Teno-DF. This eventually raises the cost of the materials.
It is reported that tenofovir disoproxil (Teno-D, MP 61-65° C., MW 519.45) with low purity causes formation of degradation products during its storage to produce Teno-D dimer that serves as a polymer itself (Organic Process Research & Development. 2010, Vol. 14, 1194-1201, Pharmaceutical Research, 2001, Vol. 18, 234-237).